CS252920B1 - Process for the preparation of 4- (4-substituted 3-oxo-1-buten-1-yl) -2H-hexahydroylcyclopentyl] furan-2-one - Google Patents

Abstract

The method for producing 4-/4-substituted- -3-oxo-1-buten-1-yl/-2H-hexahydrocyclopenta/b/furan-2-ones of the general formula I, where R denotes an η-butyl-, 3-chlorophenoxy-, 3-trifluoromethylphenoxy- group, by oxidation of the 15R- -isomer of the enol of the general formula II, where R has the above-mentioned meaning, consists in that the aene of the compound of the general formula II in a chlorinated hydrocarbon environment is reacted in situ with a 1:1 to 1.1 chlorine-thionisole complex prepared in situ at a temperature of -40 to -25 °C, whereby 0.5 to 0.6 mol of the compound of the general formula II is used per 1 mol of the complex, after which a solution of a tertiary amine in a chlorinated hydrocarbon is added to the reaction mixture after 0.5 to 2 hours and after heating the reaction mixture to room temperature, the organic phase is gradually extracted with a solution containing 0.5 to 2% by weight of hydrochloric or sulfuric acid, 0.06 to 0.20 M sodium or potassium pyrosulfite solution, water and after evaporation of the solvents, the product of general formula I is obtained by crystallization.

Description

The present invention relates to a process for the preparation of 4- (4-substituted-3-oxo-1-buten-1-yl) -2H-hexahydrocyclopenta (b) furan-2-ones of the general formula I, wherein R is tert-butyl, 3-chlorophenoxy-, 3-trifluoromethylphenoxy- group by oxidation of the 15R-isomer of enol of formula (II) (prostaglandin numbering), wherein R is as defined above, eliminated in the production of intermediates for synthesis without glandin, α ^, α ^{and β} analogs. Prostaglandins are a group of highly biologically active compounds currently used in both human and veterinary medicine / Chem. Eng. News Aug 16, p. 30 (1982), Prostaglandins and Thromboxanes (Sds SMRoberts, RF Newton / Butterworths, London 1982, Contact / Merck / 1983/2/50).

The oxidation of the 15R-isomer of the enol of formula (II) is carried out with chromium trioxide in dilute sulfuric acid and low boiling ketone, preferably acetone (AO 223 403). The disadvantage of this process is, on the one hand, the relatively difficult separation of the chromium salts from the desired product and, on the other hand, the requirement for their perfect removal from the waste water. Another method uses a ketone to oxidize the 15R-enol of formula II in the presence of aluminum tri-alkanolates (Oppennauer oxidation). In this embodiment, it is necessary to use a considerable excess of anhydrous reagents and solvents, while isolating the product from the reaction mixture is relatively laborious.

These processes are followed by the process according to the invention, which comprises adding to the in situ prepared chlorine-thioanisole complex in a molar ratio of components of 1: 1 to 1.1 in a chlorinated hydrocarbon at -40 to -25 ° C with stirring. The 15R-isomer of enol of formula (II), wherein from 0.5 to 0.6 mol of the compound of formula (I) is used per mole of the above complex

232 920 of formula II. After the oxidation is complete in 0.5 to 2 hours, an amine preferably triethylamine or diisopropylethylamine in the above solvent is added dropwise to the reaction mixture at the above temperature, after which the cooling bath is removed and the reaction mixture is slowly warmed to room temperature. The chlorinated hydrocarbon used as solvent contains 1 to 2 carbon atoms and 2 to 4 chlorine atoms, preferably 1,2-dichloroethane, dichloromethane or carbon tetrachloride, or mixtures thereof. After completion of the reaction, the organic phase is washed successively with a solution containing 0.5 to 2 wt. hydrochloric or sulfuric acid, 0.06-0.20 M sodium or potassium pyrosulphite solution, water and, if necessary, dried over sodium or magnesium sulphate, the solvents are evaporated on a vacuum evaporator. Crystallization of the distillation residue from an aliphatic hydrocarbon containing from 5 to 10 carbon atoms such as pentane, hexane, cyclohexane, decane or mixtures thereof gives a crystalline product of the formula I in high yield and purity.

The advantage of the process according to the invention is that it is easy to carry out the reaction on a technological scale, requiring no complex equipment, using readily available and inexpensive reagents. Together with simple isolation and high yields it is highly profitable.

The process according to the invention is demonstrated in several specific examples which are illustrative only.

Example 1

To a solution of 9.0 g of chlorine in 250 ml of 1,2-dichloroethane, 17 g of thioanisole in 50 ml of the same solvent was added dropwise at -20 ° C. After cooling the reaction mixture to -35 to -30 ° C, 35 g of a compound of formula II wherein R is 3-chlorophenoxy in 300 ml of the above solvent was added dropwise and after stirring for 1.5 hours 30 g was added dropwise. of triethylamine in 60 ml of 1,2-dichloroethane. After removal of the cooling bath and spontaneous warming of the reaction mixture to room temperature, the organic phase was washed successively with 50 ml of about 1% hydrochloric acid, 100 ml of about 0.1 M

252 920

- 3 sodium pyrosulphite, 100 ml water and solvent evaporated on a rotary evaporator (bath temperature 50-5 ° C and pressure 1.3 to 2 kPa) to a volume of 80 to 100 ml. Subsequently, 100 hexane was added to the distillation residue and thoroughly hydrogenated. The precipitated crystals were aspirated, washed with 30 ml of the same solvent, and dried to give 34 g containing 97% of the product of formula I wherein R is 3-chlorophenoxy. The percentage determination was carried out by means of high pressure liquid chromatography.

Example 2 ^k

To a solution of 9.72 g of chlorine in 200 mL of dichloromethane-tetra chloromethane (1: 1) at -20-2 ° C was added 17 g of thioanisole in 45 mL of the same solvent. After cooling the reaction mixture to 55 [deg.] C and 5 [deg.] C, 37.3 of the compound of formula II wherein R is 3-trifluoromethylphenoxy in 340 ml of dichloromethane were added and after stirring for 1 hour at the above temperature, the reaction mixture was worked up as in Example 1. From the distillation residue suspended in cyclohexane, 35.1 g was obtained with a content of 95.7% of the product of formula I wherein R is 3-trifluoromethylphenoxy.

Claims (3)

OBJECT OF THE INVENTION 252 920 A process for the preparation of 4- (4'-substituted-5-oxo-1-buten-1-yl) -2H-hexahydrocyclopenta (b) furan-2-ones of the formula I wherein R is tert-butyl-, 3-chlorophenoxy-, 5-trifluoromethylphenoxy, by oxidation of the 15R-isomer of an enol of formula (II) wherein R is as defined above, wherein the compounds of formula (II) in a chlorinated hydrocarbon environment are treated in situ with a 1: 1 to 1.1 chlorine complex with thioanisole at -40 to -25 ° C using 0.5 to 0.6 mole of the compound of formula II per mole of complex, followed by a solution of tertiary amine in chlorinated after 0.5 to 2 hours After the reaction mixture is warmed to room temperature, the organic phase is successively extracted with a solution containing 0.5 to 2 wt. hydrochloric or sulfuric acid, with a 0.06-0.20 M sodium or potassium pyrosulphite solution, water and, after evaporation of the solvents, the product of formula I is obtained by crystallization. 2. A process according to claim 1 wherein the tertiary amine is triethylamine or diisopropylethylamine. 5. A process according to claim 1, wherein the product is crystallized using an aliphatic hydrocarbon containing from 5 to 10 carbon atoms such as pentane, hexane, cyclohexane, decane or a mixture thereof.